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J. Biol. Chem., Vol. 281, Issue 34, 24254-24269, August 25, 2006

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The Circadian Clock within the Cardiomyocyte Is Essential for Responsiveness of the Heart to Fatty Acids^*

David J. Durgan¹, Nowice A. Trexler¹, Oluwaseun Egbejimi, Tracy A. McElfresh, Hee Yun Suk^¶, Lauren E. Petterson, Chad A. Shaw^||, Paul E. Hardin^**, Molly S. Bray, Margaret P. Chandler, Chi-Wing Chow^¶, and Martin E. Young²

From the United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, the Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, the ^¶Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, the ^||Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, and the ^**Department of Biology, Texas A & M University, College Station, Texas 77204

Cells/organs must respond both rapidly and appropriately to increased fatty acid availability; failure to do so is associated with the development of skeletal muscle and hepatic insulin resistance, pancreatic-cell dysfunction, and myocardial contractile dysfunction. Here we tested the hypothesis that the intrinsic circadian clock within the cardiomyocytes of the heart allows rapid and appropriate adaptation of this organ to fatty acids by investigating the following: 1) whether circadian rhythms in fatty acid responsiveness persist in isolated adult rat cardiomyocytes, and 2) whether manipulation of the circadian clock within the heart, either through light/dark (L/D) cycle or genetic disruptions, impairs responsiveness of the heart to fasting in vivo. We report that both the intramyocellular circadian clock and diurnal variations in fatty acid responsiveness observed in the intact rat heart in vivo persist in adult rat cardiomyocytes. Reversal of the 12-h/12-h L/D cycle was associated with a re-entrainment of the circadian clock within the rat heart, which required 5–8 days for completion. Fasting rats resulted in the induction of fatty acid-responsive genes, an effect that was dramatically attenuated 2 days after L/D cycle reversal. Similarly, a targeted disruption of the circadian clock within the heart, through overexpression of a dominant negative CLOCK mutant, severely attenuated induction of myocardial fatty acid-responsive genes during fasting. These studies expose a causal relationship between the circadian clock within the cardiomyocyte with responsiveness of the heart to fatty acids and myocardial triglyceride metabolism.

Received for publication, February 22, 2006 , and in revised form, June 6, 2006.

^* This work was supported by American Heart Association Texas Affiliate Beginning Grant-in-aid Award 0365028Y and by NHBLI Grant HL-074259-01 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–6.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Dept. of Pediatrics, 1100 Bates St., Houston, TX 77030. Tel.: 713-798-7567; Fax: 713-798-7101; E-mail: meyoung{at}bcm.edu.

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